Nk-3 receptor antagonists for therapeutic treatment of leptin-related disease

ABSTRACT

Disclosed is use of NK3R antagonists for the therapeutic treatment leptin-related disease.

FIELD OF INVENTION

The present invention relates to the field of products dedicated to thetreatment of excess body fat and/or of excess body weight, especiallythe treatment of excess body fat and/or the prevention of body fat gain.The present invention also relates to a cosmetic method for improving orslimming the figure and/or stimulating the loss of excess body weight,especially for stimulating the loss of excess body fat.

Especially, the invention relates to the use of NK-3 receptorantagonists (also referred to as NK3R antagonists) for the therapeuticor cosmetic treatment of excess body fat and/or of excess body weight,preferably for the therapeutic treatment of excess body fat and/or theprevention of body fat gain in patients. More specifically, theinvention relates to the use, to decrease body fat and/or prevent fatgain, of selective NK3R antagonists or pharmacologically acceptablesalts or solvates thereof, previously described in international patentapplications WO 2011/121137, WO 2013/050424, WO 2014/154895,WO2014/154896 and WO2014/154897 in the name of the Applicant.

BACKGROUND OF INVENTION

Weight gain is a growing problem in the world population, especially inNorth America and Europe. Excess body weight, particularly in abdominalfat, is associated with a number of comorbidities including asignificantly elevated risk for type 2 diabetes, coronary heart disease,stroke, hypertension, various types of cancer and numerous other majorillnesses, and overall mortality from all causes (Must et al, 1999, JAMA282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1 105).

Existing therapies for the treatment and/or prevention of weight gaininclude for example GLP-1 agonists and central neurotransmittermodulators such as Contrave or Lorcaserin. However, these medicinesgenerally elicit modest weight loss (3-8% after one year of treatment)and are associated with safety concerns including pancreatitis andcardiovascular effects (GLP-1 agonists) and changes in mood and/orcognition for the neurotransmitter modulators.

Non-medicinal therapies include standard diets and exercise, very lowcalorie diets, behavioral therapy, pharmacotherapy involving appetitesuppressants, thermogenic drugs, food absorption inhibitors, mechanicaldevices such as jaw wiring, waist cords and balloons, and gastric bypasssurgery. However, these non-medicinal therapies, although widely usedare not very effective. Adherence to energy restriction diets isproblematic and generally unsuccessful and the efficacy of gastricbypass surgery tends to wane over time with regard to long-term weightmanagement.

The development of novel medicines for the treatment of excess bodyweight have often been limited by toxicity and side effects includingtachycardia (increased heart rate), pulmonary hypertension, heart valvedamage, and drug dependency (addiction).

Therefore, there remains a need for new products useful for treatingand/or preventing excess body fat and/or of excess body weight.

Localized fat accumulations may also occur in a non-pathological manner(i.e. non-associated with an increased burden of disease) in individualsbeing in good health with a normal corpulence, according to the WHOstandards. Such fat accumulation, although not directly affecting thehealth, may be considered as being unaesthetic. Therefore, it is alsouseful to develop cosmetic methods to allow people who are in goodhealth to stabilize weight and to stay thin without localized fatdeposits.

Such therapeutic or cosmetic strategies will be all the more useful asthey will make it possible to preferably target body fat loss whilepreserving the lean body mass.

Surprisingly, the Applicant have found that the selective antagonism ofthe neurokinin-3 receptor (NK3R), is beneficial in weight control,specifically with regard to a reduction in body fat. The NK3 receptor isa target known to modulate the hypothalamic-pituitary-gonadal axis (HPGaxis), which is of relevance to body metabolism. The Applicant alsoevidenced that the use of NK3R antagonists increases circulating leptinlevels, which may explain the observed effect on weight and body fat.Indeed, leptin is known to be the “satiety hormone” which enables toachieve energy homeostasis and which able to trigger impressive weightloss in some patient.

The present invention is all the more surprising that inhibition ornegative modulation of other targets known to modulate the HPG axissimilarly to NK3 receptor is conversely reported to lead to an increasein weight gain. This was especially shown for the GnRH receptor (Ozonoet al., 2012, Jpn J Clin Oncol 42:477-84; Tascilar et al., 2011, Turk JPediatrics) and for the Kisspeptin (GPR54) receptor (Tolson et al.,2014; J Clin Invest 124:3075-3079).

Besides, a study showed that NK3-knockout mice underwent weight increase(Siociak et al., Psychopharmacology, 2007, 197, 185-195). This result isnot contradictory with the findings of the present invention since thegenetic deletion of the NK3 receptor cannot be assimilated to thepharmacological inhibition of a receptor activity by an NK3R antagonist,since genetic deletion of a receptor induces a lot of other changes.

Another study was conducted on rats fed with a standard chow diet or fedwith a high-fat diet to which SB222200 NK3R antagonist was administered(Li et al., J. Neuroendocrinology, 2014, 26, 521-527). In this study, noeffect on weight was observed. SB222200 NK3R antagonist is known to havea non-optimal pharmacological profile, which, may explain the absence ofeffects on weight observed in rats for SB222200.

Moreover, the present invention is all the more surprising that despitethe previous drug development and clinical testing of various NK3Rantagonists, it was never previously disclosed that NK3R antagonists maybe beneficial in weight control, specifically with regards of reductionof body fat and so prevention of body fat gain.

The current invention demonstrates for the first time that the use of anNK3R antagonist prevents adiposity-induced weight gain. It is alsoevidenced that the use of an NK3R antagonist enables weight loss byreduction of fat mass, without substantial muscle loss.

SUMMARY

This invention thus relates to a NK-3 receptor antagonist for use in thetherapeutic treatment of excess body weight and/or excess body fat.Especially, the invention relates to a NK-3 receptor antagonist for usein the therapeutic treatment of excess body fat or in the prevention ofbody fat gain in patients; provided that the NK-3 receptor antagonist isnot 3-Methyl-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide.

According to one embodiment, the NK-3 receptor antagonist is selectedfrom the group consisting of:

-   -   (a)        3-Methyl-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide    -   (b)        (R)-N-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenyl        piperidin-4-yl)-N-methylacetamide    -   (c) (R)-[[2-Phenyl-4-quinolinyl)carbonyl]amino]-methyl ester        benzeneacetic acid    -   (d)        N1-[1-3-R3R)-1-Benzoyl-3-(3-(3,4-dichlorophenyl)-3-piperidinyl]propyl]-4-phenyl-piperidinyl]-N,N-dimethylurea        hydrochloride    -   (e)        3-methanesulfonamido-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide    -   (f)        3-Hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide    -   (g) methyl        2-(3-((4-(tert-butyl)piperazin-1-yl)methyl)-8-fluoro-2-phenylquinoline-4-carbonyl)-1-phenylhydrazinecarboxylate    -   (h) compounds of general formula A:

-   -   -   wherein R₁ represents ethyl, cylopropyl or cyclobutyl;        -   wherein R₁₂ represents fluoro or chloro; and        -   R₁₃, R₁₄ and R₁₅ each individually represent hydrogen,            fluoro or chloro,        -   wherein two of R₁₃, R₁₄ and R₁₅ represent hydrogen;

    -   (i) compounds of general formula I:

-   -   -   wherein        -   Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to            6-membered cycloalkyl group a 3- to 6-membered heterocyclyl            group or a C3-C6 alkyl group, each of the aryl, heteroaryl,            cycloalkyl or heterocyclyl groups being optionally            substituted by one or more group(s) selected from halo,            cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl,            aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy,            alkoxyalkoxy, alkylamino, carboxy, alkoxycarbonyl,            alkylcarbonyloxy, alkylcarbonylamino,            haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,            carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,            haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,            alkylsulfonylamino, haloalkylsulfonylamino, or two            substituents form an alkylenedioxy group or a            haloalkylenedioxy group, or two substituents form a            cycloalkyl or heterocycloalkyl moiety together with the            cycloalkyl or heterocycloalkyl group they are attached to,            or fused to the aryl, heteroaryl, cycloalkyl or            heterocycloalkyl group may be one or more aryl moiety, each            of said substituents being optionally substituted by one or            more further substituent(s) selected from halo, cyano,            alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy,            heterocyclyl, aryl, heteroaryl, aryloxy or heteroaryloxy;        -   L¹ is C₁-C₂ alkylene optionally being substituted by one or            more group(s) selected from halo, methyl or ethyl under the            condition that R^(2′) together with R² form an oxo            substituent, or L¹ is carbonyl or sulfonyl, or L¹ is            —(C═O)—CH₂— where the C═O is linked to the piperazine            nitrogen and the CH₂ to Ar¹;        -   R¹ is H, a C₁-C₄ alkyl, aryl or aralkyl group, each of said            alkyl, aryl or aralkyl groups being optionally substituted            by one or more group(s) selected from halo or hydroxyl;        -   R^(1′) is H or a C₁-C₄ alkyl group;        -   R² is H or a C₁-C₄ alkyl group;        -   R^(2′) is H or a C₁-C₄ alkyl group, or, when L¹ is C₁-C₂            alkylene optionally being substituted by one or more            group(s) selected from halo, methyl or ethyl, R^(2′)            together with R² form an oxo substituent;        -   R³ is H or a C₁-C₄ alkyl group optionally substituted by one            hydroxy;        -   R^(3′) is H or a C₁-C₄ alkyl group;        -   X¹ and X² are independently selected from N or C—Z wherein Z            is H or C₁-C₂ alkyl under the condition that X¹ and X²            cannot be both C—Z;        -   L² is a single bond or carbonyl;        -   Ar^(e) is a 5- to 6-membered aryl or heteroaryl group, each            of the aryl, or heteroaryl groups being optionally            substituted by one or more group(s) selected from halo,            cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,            heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,            hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy,            alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,            haloalkylcarbonylamino, acylamino, carbamoyl,            alkylcarbamoyl, carbamoylalkyl, carbamoylamino,            alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,            arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl,            alkylsulfonylamino, haloalkylsulfonylamino, or two            substituents form an alkylenedioxy group or a            haloalkylenedioxy group, or fused to the aryl or heteroaryl            group may be one or more cycloalkyl, aryl, heterocyclyl or            heteroaryl moiety, each of said substituents being            optionally substituted by one or more further substituent(s)            selected from halo, cyano, alkyl, haloalkyl, alkoxy,            haloalkoxy, cycloalkyl, heterocyclyl optionally substituted            by alkyl, aryl, heteroaryl, hydroxyl, alkoxyalkyl,            hydroxyalkoxy, alkylamino, alkylsulfonylamino,            alkoxycarbonylamino, aminoalkoxy, or            alkoxycarbonylaminoalkoxy;

    -   and stereoisomers, mixture of stereoisomers, prodrugs,        pharmaceutically acceptable salts, hydrates, solvates, acid salt        hydrates, N-oxides and isomorphic crystalline forms thereof.

According to one embodiment, the NK-3 receptor antagonist is selectedfrom the group consisting of (b), (c), (d), (e), (f), (g), (h) and (i)as defined above.

According to one embodiment, the NK-3 receptor antagonist is of formulaI as defined above, and pharmaceutically acceptable salts and solvatesthereof.

According to one embodiment, the NK-3 receptor antagonist is of formulaIII

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl;    -   X¹ is N and X² is S or 0; or X¹ is S and X² is N;    -   represents a single or a double bound depending on X¹ and X²;    -   stands for the (R)-enantiomer or for the racemate of compound of        formula III.

According to one embodiment, the NK-3 receptor antagonist for useaccording to the invention is under the form of a pharmaceuticalcomposition comprising the NK-3 receptor antagonist and at least onepharmaceutically acceptable vehicle.

According to one embodiment, the NK-3 receptor antagonist is for thetreatment of patients suffering from pathological excess of body fatand/or of excess body weight. According to one embodiment, the NK-3receptor antagonist is for the treatment of patients suffering frompathological excess of body fat or for the prevention of body fat gainin patients prone to suffer from pathological excess body fat.

According to one embodiment, patients suffering from pathological excessof body fat and/or of excess body weight are selected from individualssuffering from hormonal imbalance; individuals suffering from geneticsusceptibility to excess body weight; and individuals where anadipose-specific decrease in weight is deemed to be of therapeuticbenefit. According to one embodiment, patients suffering frompathological excess of body fat or patients prone to suffer frompathological excess body fat are selected from individuals sufferingfrom hormonal imbalance; individuals suffering from geneticsusceptibility to excess body weight; and individuals where anadipose-specific decrease in weight is deemed to be of therapeuticbenefit.

According to one embodiment, individuals suffering from hormonalimbalance are selected from women subjected to estrogen-loweringtherapies; and women experiencing natural, age-related decreases inestrogen.

According to one embodiment, individuals suffering from hormonalimbalance are selected from women that undergo changes in ovarianhormone levels.

According to one embodiment, individuals suffering from hormonalimbalance are selected from men subjected to androgen-loweringtherapies; and men experiencing natural, age-related decreases incirculating testosterone.

According to one embodiment, individuals where an adipose-specificdecrease in weight is deemed to be of therapeutic benefit are selectedfrom overweight individuals; individuals receiving medical treatmentsthat are accompanied with weight gain comprising but not limited tohormonal treatment as well as steroids, pain or antipsychoticmedications; individuals having inappropriate eating behaviors.

According to one embodiment, patients are leptin-sensitive patients,preferably leptin sensitive women patients.

The invention also relates to a NK-3 receptor antagonist for use in thetreatment of a leptin-related disease.

According to one embodiment, the leptin-related disease is selected frommetabolic disorders such as diabetes, cardiovascular diseases ormetabolic syndrome; lipid regulation disorders such as lipodystrophy,including congenital and acquired lipodystrophy, dyslipidemia,nonalcoholic fatty liver disease, nonalcoholic steatohepatitis orhyperlipidemia; Congenital Leptin Deficiency; hypothalamic amenorrhea,including exercise-induced hypothalamic amenorrhea, Rabson-Mendenhallsyndrome; and osteoporosis.

According to one embodiment, the NK-3 receptor antagonist for use in thetreatment of a leptin-related disease is selected from the groupconsisting of (b), (c), (d), (e), (f), (g), (h) and (i) as definedabove.

According to one embodiment, in the treatment of leptin-relateddiseases, the NK-3 receptor antagonist is of formula I as defined above,and pharmaceutically acceptable salts and solvates thereof. According toone embodiment, in the treatment of leptin-related diseases, the NK-3receptor antagonist is of formula III, as defined above. According to aspecific embodiment, in the treatment of leptin-related diseases, theNK-3 receptor antagonist is k-5.

The invention also relates to a cosmetic treatment method for improvingthe bodily appearance by stimulating the loss of body weight and/or ofbody fat in a subject, comprising the administration to said subject ofa NK-3 receptor antagonist, and optionally the renewal of saidadministration until the expected cosmetic effect is obtained.Especially, the invention relates to a cosmetic treatment method forimproving the bodily appearance by stimulating the loss of body weightand/or of body fat in a subject, comprising the administration to saidsubject of a NK-3 receptor antagonist, and optionally the renewal ofsaid administration until the expected cosmetic effect is obtained,provided that the NK-3 receptor antagonist is not3-Methyl-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide

According to one embodiment, in the cosmetic treatment method of theinvention, the subject is an individual being in good health and havinga BMI from 18.5 to 25 kg/m².

According to one embodiment, in the cosmetic treatment method of theinvention, the NK-3 receptor antagonist is selected from the groupconsisting of:

-   -   (a)        3-Methyl-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide    -   (b)        (R)-N-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenyl        piperidin-4-yl)-N-methylacetamide    -   (c) (R)-[[2-Phenyl-4-quinolinyl)carbonyl]amino]-methyl ester        benzeneacetic acid    -   (d)        N1-[1-3-[(3R)-1-Benzoyl-3-(3-(3,4-dichlorophenyl)-3-piperidinyl]propyl]-4-phenyl-piperidinyl]-N,N-dimethylurea        hydrochloride    -   (e)        3-methanesulfonamido-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide    -   (f)        3-Hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide    -   (g) methyl        2-(3-((4-(tert-butyl)piperazin-1-yl)methyl)-8-fluoro-2-phenylquinoline-4-carbonyl)-1-phenylhydrazinecarboxylate    -   (h) compounds of general formula A, as defined above    -   (i) compounds of general formula I, as defined above;    -   and stereoisomers, mixture of stereoisomers, prodrugs,        pharmaceutically acceptable salts, hydrates, solvates, acid salt        hydrates, N-oxides and isomorphic crystalline forms thereof.

According to one embodiment, in the cosmetic treatment method of theinvention, the NK-3 receptor antagonist is selected from the groupconsisting of (b), (c), (d), (e), (f), (g), (h) and (i) as definedabove.

According to one embodiment, in the cosmetic treatment method of theinvention, the NK-3 receptor antagonist is of formula I as definedabove, and pharmaceutically acceptable salts and solvates thereof.

According to one embodiment, in the cosmetic treatment method of theinvention, the NK-3 receptor antagonist is of formula III, as definedabove.

DEFINITIONS

The definitions and explanations below are for the terms as usedthroughout the entire application, including both the specification andthe claims.

The term “NK3R antagonist” or “NK-3 receptor antagonist” refers to acompound that can bind to a neurokinin B receptor (NK3R) but has littleor no functional activity of its own at the receptor—thus disrupting,blocking or otherwise interfering with the action of the naturallyoccurring, endogenous ligand (i.e., NKB). Preferably the NK3R antagonistis a compound which competitively or non-competitively binds to the NK3Rat the same site as an agonist (for example, the endogenous ligand), butdoes not activate an intracellular response initiated by an active formof the receptor. An antagonist thereby inhibits the intracellularresponse induced by an agonist.

When describing the NK3R antagonists, the terms used are to be construedin accordance with the following definitions, unless indicatedotherwise.

Where groups may be substituted, such groups may be substituted with oneor more substituents, and preferably with one, two or threesubstituents. Substituents may be selected from but not limited to, forexample, the group comprising halogen, hydroxyl, oxo, nitro, amido,carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each beingoptionally substituted with . . . ” or “alkyl, aryl, or cycloalkyl,optionally substituted with . . . ” encompasses “alkyl optionallysubstituted with . . . ”, “aryl optionally substituted with . . . ” and“cycloalkyl optionally substituted with . . . ”.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.Preferred halo groups are fluoro and chloro.

The term “alkyl” by itself or as part of another substituent refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numbergreater than or equal to 1. Generally, alkyl groups of this inventioncomprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms,more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2carbon atoms. Alkyl groups may be linear or branched and may besubstituted as indicated herein.

Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g.n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl,iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl,propyl, n-butyl, i-butyl, s-butyl and t-butyl. C_(x-y)-alkyl andCx-Cy-alkyl refer to alkyl groups which comprise from x to y carbonatoms.

When the suffix “ene” (“alkylene”) is used in conjunction with an alkylgroup, this is intended to mean the alkyl group as defined herein havingtwo single bonds as points of attachment to other groups. The term“alkylene” includes methylene, ethylene, methylmethylene, propylene,ethylethylene, and 1,2-dimethylethylene.

The term “haloalkyl” alone or in combination, refers to an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. Examples of such haloalkylradicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.C_(x-y)-haloalkyl and Cx-Cy-alkyl refer to alkyl groups which comprisefrom x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl,trifluoromethyl.

The term “cycloalkyl” as used herein is a cyclic alkyl group, that is tosay, a monovalent, saturated, or unsaturated hydrocarbyl group having 1or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclichydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbonatoms in the ring and generally, according to this invention comprisefrom 3 to 10, more preferably from 3 to 8 carbon atoms still morepreferably from 3 to 6 carbon atoms. Examples of cycloalkyl groupsinclude but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, with cyclopropyl being particularly preferred.

When the suffix “ene” is used in conjunction with a cyclic group, thisis intended to mean the cyclic group as defined herein having two singlebonds as points of attachment to other groups. Therefore,“cycloalkylene” herein refers to a saturated homocyclic hydrocarbylbiradical of Formula C_(n)H_(2n-2). Suitable cycloalkylene groups areC₃₋₆ cycloalkylene group, preferably a C₃₋₅ cycloalkylene (i.e.1,2-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene,1,2-cyclobutylene, 1,3-cyclobutylene, 1,3-cyclopentylene, or1,1-cyclopentylene), more preferably a C₃₋₄ cycloalkylene (i.e.1,2-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene,1,2-cyclobutylene).

Where at least one carbon atom in a cycloalkyl group is replaced with aheteroatom, the resultant ring is referred to herein as“heterocycloalkyl” or “heterocyclyl”.

The terms “heterocyclyl”, “heterocycloalkyl” or “heterocyclo” as usedherein by itself or as part of another group refer to non-aromatic,fully saturated or partially unsaturated cyclic groups (for example, 3to 7 member monocyclic, 7 to 11 member bicyclic, or containing a totalof 3 to 10 ring atoms) which have at least one heteroatom in at leastone carbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. Any of the carbon atoms of the heterocyclicgroup may be substituted by oxo (for example piperidone,pyrrolidinone).The heterocyclic group may be attached at any heteroatomor carbon atom of the ring or ring system, where valence allows. Therings of multi-ring heterocycles may be fused, bridged and/or joinedthrough one or more spiro atoms. Exemplary heterocyclic groups includeoxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinylimidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl,isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl,2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl,4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl,2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl,tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl,tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl,thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide,thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl,1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl,and morpholin-4-yl.

The ring atoms of selected heterocyclyl and heterocyclylene moieties arenumbered based on scheme below:

The ring atoms of fused piperazine are numbered based on scheme below

The term “aryl” as used herein refers to a polyunsaturated, aromatichydrocarbyl group having a single ring (i.e. phenyl) or multiplearomatic rings fused together (e.g. naphtyl) or linked covalently,typically containing 5 to 12 atoms; preferably 6 to 10, wherein at leastone ring is aromatic. The aromatic ring may optionally include one totwo additional rings (either cycloalkyl, heterocyclyl or heteroaryl)fused thereto. Aryl is also intended to include the partiallyhydrogenated derivatives of the carbocyclic systems enumerated herein.Examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1-2-, 3-,4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4-or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl,1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or5-pyrenyl.

The term “arylene” as used herein is intended to include divalentcarbocyclic aromatic ring systems such as phenylene, biphenylylene,naphthylene, indenylene, pentalenylene, azulenylene and the like.Arylene is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems enumerated above. Examples ofsuch partially hydrogenated derivatives are1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

Where at least one carbon atom in an aryl group is replaced with aheteroatom, the resultant ring is referred to herein as a heteroarylring.

The term “heteroaryl” as used herein by itself or as part of anothergroup refers but is not limited to 5 to 12 carbon-atom aromatic rings orring systems containing 1 to 2 rings which are fused together or linkedcovalently, typically containing 5 to 6 atoms; at least one of which isaromatic, in which one or more carbon atoms in one or more of theserings is replaced by oxygen, nitrogen and/or sulfur atoms where thenitrogen and sulfur heteroatoms may optionally be oxidized and thenitrogen heteroatoms may optionally be quaternized. Such rings may befused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Examplesof such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl,pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl,triazinyl, imidazo[2,1-b ][1,3]thiazolyl, thieno[3,2-b]furanyl,thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl,thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl,indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl,isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl,1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl,1,2-benzoisothiazolyl, 2,1-benzoisothiazolyl, benzotriazolyl,1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl,2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl,imidazo[1,2-alpyridinyl, 6-oxo-pyridazin-1(6H)-yl,2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl,1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,quinoxalinyl.

The term “heteroarylene” as used herein means divalent carbocyclicaromatic ring systems including pyridinylene and the like.

The ring atoms of selected heteroaryl or heteroarylene moieties arenumbered on scheme below:

The term “carbamoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “thiophen-2-yl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The NK3R antagonists may contain an asymmetric center and thus may existas different stereoisomeric forms. Accordingly, the present inventionincludes all possible stereoisomers and includes not only racemiccompounds but the individual enantiomers and their non-racemic mixturesas well. When a compound is desired as a single enantiomer, such may beobtained by stereospecific synthesis, by resolution of the final productor any convenient intermediate, or by chiral chromatographic methods aseach are known in the art.

The bonds from an asymmetric carbon may be depicted herein using a solidline (-), a zigzag line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds from an asymmetric carbonatom is meant to indicate that all possible stereoisomers in anyrelative ratio are meant to be included, unless it is clear from thecontext that a specific stereoisomer is intended. As an example, a solidline depicting bonds from an asymmetric carbon atom in a compoundcontaining one asymmetric carbon encompasses a racemic mixture of bothenantiomers. The term racemic used herein indicated a 1/1 ratio betweenthe two enantiomers. The use of either a solid or dotted wedge to depictbonds from an asymmetric carbon atom is meant to indicate that only thestereoisomer shown is meant to be included.

The NK3R antagonists may be in the form of pharmaceutically acceptablesalts. Pharmaceutically acceptable salts include the acid addition andbase salts thereof. Suitable acid addition salts are formed from acidswhich form non-toxic salts. Examples include the acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts. Suitable base salts are formedfrom bases which form non-toxic salts. Examples include the aluminium,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. Preferred, pharmaceutically acceptable salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, and acetate.

When the NK3R antagonists contain an acidic group as well as a basicgroup the NK3R antagonists may also form internal salts, and suchcompounds are within the scope of the invention. When the NK3Rantagonists contain a hydrogen-donating heteroatom (e.g. NH), theinvention also covers salts and/or isomers formed by transfer of saidhydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of may be prepared by one or more ofthese methods:

-   -   (i) by reacting the compound with the desired acid;    -   (ii) by reacting the compound with the desired base;    -   (iii) by removing an acid- or base-labile protecting group from        a suitable precursor of the compound or by ring-opening a        suitable cyclic precursor, for example, a lactone or lactam,        using the desired acid; or    -   (iv) by converting one salt of the compound to another by        reaction with an appropriate acid or by means of a suitable ion        exchange column.

All these reactions are typically carried out in solution. The salt, mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The term “solvate” is used herein to describe a molecular complexcomprising the compound of interest and one or more pharmaceuticallyacceptable solvent molecules, for example, ethanol. The term “hydrate”is employed when said solvent is water.

In addition, although generally, with respect to the salts of thecompounds of interest, pharmaceutically acceptable salts are preferred,it should be noted that the invention in its broadest sense alsoincluded non-pharmaceutically acceptable salts, which may for example beused in the isolation and/or purification of the compounds of interest.For example, salts formed with optically active acids or bases may beused to form diastereoisomeric salts that can facilitate the separationof optically active isomers of the compounds.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the NK3R antagonists.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of the compound of interest such as esters whose in vivobiotransformation product is the active drug. Prodrugs are characterizedby increased bio-availability and are readily metabolized into theactive compounds in vivo. Suitable prodrugs for the purpose of theinvention include carboxylic esters, in particular alkyl esters, arylesters, acyloxyalkyl esters and dioxolene carboxylic esters; ascorbicacid esters; thioesters such as alkylthio esters or aryl thioesters; andamides.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The term “pharmaceutically acceptable” means approved or approvable by aregulatory agency or listed in recognized pharmacopeia for use inanimals, and more preferably in humans. It can be material which is notbiologically or otherwise undesirable, i.e. the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “physiologically acceptable” refers to a medium which has notoxic or detrimental effect in the conditions of use and which is inerttowards the active substance. Such a medium may for example comprisevarious additives depending on its purpose, such as flavors, coloringagents, fillers, preservatives, diluents, wetting agents or suspendingagents, etc. Such media may also enable an immediate release, a modifiedrelease or a controlled release of one of the active substance.

The term “human” refers to subject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The term “administration”, or a variant thereof (e.g.,“administering”),means providing the active agent or active ingredient (e.g. a NK-3antagonist), alone or as part of a composition, to the subject orpatient in need thereof.

DETAILED DESCRIPTION

The present invention relates to the use of NK-3 receptor antagonists(also herein referred to as NK3R antagonists) for the therapeutic orcosmetic treatment of excess body fat and/or of excess body weight,preferably for the therapeutic treatment of excess body fat and/orprevention of body fat gain. Suitable NK3R antagonists and formulationsthereof are described below.

NK3R Antagonists

Any suitable NK3R antagonist can be used in the therapeutic and cosmeticmethods of the invention. By “suitable NK3R antagonist”, it is referredto a NK3R antagonist which has a suitable pharmacological profile andespecially that cross the brain barrier. Especially, any NK3R antagonistmay be used, including but not limited to stereoisomers, mixture ofstereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates,solvates, acid salt hydrates, N-oxides and isomorphic crystalline formsthereof.

According to one embodiment, the NK3R antagonist is selected from thegroup comprising non-peptide small molecule antagonists including butnot limited to stereoisomers, mixture of stereoisomers, prodrugs,pharmaceutically acceptable salts, hydrates, solvates, acid salthydrates, N-oxides and isomorphic crystalline forms thereof; as well aspeptide NK3R antagonists.

According to one embodiment, NK3R antagonists used in the presentinvention are selective NK3R antagonists. By “selective NK3R antagonist”it is referred to an antagonist of the NK3 receptor which is selectiveover NK1 and/or NK2 receptors.

According to one embodiment, the NK3R antagonist is selected from thegroup comprising (or stereoisomers, mixture of stereoisomers, prodrugs,pharmaceutically acceptable salts, hydrates, solvates, acid salthydrates, N-oxides and isomorphic crystalline forms thereof):

(a) SB 222200 (Available from, for example, Tocris Bioscience);3-Methyl-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide (CASNo. 174635-69-9)

(b) SR 142801 (Osanetant) (Available from, for example, Axon Medchem,Germany);(R)-N-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide (CAS No.160492-56-8)

-   -   (c) SB 218795 (Available from, for example, Tocris Bioscience);        (R)-[[2-Phenyl-4-quinolinyl)carbonyl]amino]-methyl ester        benzeneacetic acid (CAS No. 174635-53-1)

(d) SSR 146977 hydrochloride (Available from, for example, TocrisBioscience);N1-[1-3-[(3R)-1-Benzoyl-3-(3-(3,4-dichlorophenyl)-3-piperidinyllpropyl]-4-phenyl-piperidinyl]-N,N-dimethylureahydrochloride (CAS No. 264618-38-4)

(e) AZD2624 also named AZD4901 (Astra Zeneca);3-methanesulfonamido-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide(CAS No. 941690-55-7)

(f) SB 223412 (Talnetant) (Available from, for example, TocrisBioscience);3-Hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide (CASNo. 174636-32-9)

(g) compound 8m, disclosed in Elliott et al., Bioorg. Med. Chem. Lett.,2006, 16, 5752-5756; methyl2-(3-((4-(tert-butyl)piperazin-1-yl)methyl)-8-fluoro-2-phenylquinoline-4-carbonyl)-1-phenylhydrazinecarboxylate

(h) one or more of the isoquinolone derivatives NK3R antagonistsdisclosed in U.S. Pat. No. 8,420,667, of general formula A:

wherein R₁ represents ethyl, cylopropyl or cyclobutyl;

wherein R₁₂ represents fluoro or chloro; and

R₁₃, R₁₄ and R₁₅ each individually represent hydrogen, fluoro or chloro,wherein two of R₁₃, R₁₄ and R₁₅ represent hydrogen;

or a pharmaceutically acceptable salt thereof;

(i) one or more of the NK3R antagonists disclosed in WO 2011/121137, ofgeneral formula I:

and pharmaceutically acceptable salts and solvates thereof, wherein

Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-memberedcycloalkyl group a 3- to 6-membered heterocyclyl group or a C3-C6 alkylgroup, each of the aryl, heteroaryl, cycloalkyl or heterocyclyl groupsbeing optionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, aralkyl,heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino,carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or twosubstituents form an alkylenedioxy group or a haloalkylenedioxy group,or two substituents form a cycloalkyl or heterocycloalkyl moietytogether with the cycloalkyl or heterocycloalkyl group they are attachedto, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkylgroup may be one or more aryl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom halo, cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy,heterocyclyl, aryl, heteroaryl, aryloxy or heteroaryloxy;

L¹ is C₁-C₂ alkylene optionally being substituted by one or moregroup(s) selected from halo, methyl or ethyl under the condition thatR^(2′) together with R² form an oxo substituent, or L¹ is carbonyl orsulfonyl, or L¹ is —(C═O)—CH₂— where the C═O is linked to the piperazinenitrogen and the CH₂ to Ar¹;

R¹ is H, a C₁-C₄ alkyl, aryl or aralkyl group, each of said alkyl, arylor aralkyl groups being optionally substituted by one or more group(s)selected from halo or hydroxyl;

R^(1′) is H or a C₁-C₄ alkyl group;

R² is H or a C₁-C₄ alkyl group;

R^(2′) is H or a C₁-C₄ alkyl group, or, when L¹ is C₁-C₂ alkyleneoptionally being substituted by one or more group(s) selected from halo,methyl or ethyl, R^(2′) together with R² form an oxo substituent;

R³ is H or a C₁-C₄ alkyl group optionally substituted by one hydroxy;

R^(3′) is H or a C₁-C₄ alkyl group;

X¹ and X² are independently selected from N or C—Z wherein Z is H orC₁-C₂ alkyl under the condition that X¹ and X² cannot be both C—Z;

L² is a single bond or carbonyl;

Ar² is a 5- to 6-membered aryl or heteroaryl group, each of the aryl, orheteroaryl groups being optionally substituted by one or more group(s)selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, hydroxyl,alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino,carbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or two substituents form an alkylenedioxy groupor a haloalkylenedioxy group, or fused to the aryl or heteroaryl groupmay be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety,each of said substituents being optionally substituted by one or morefurther substituent(s) selected from halo, cyano, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, heterocyclyl optionally substituted byalkyl, aryl, heteroaryl, hydroxyl, alkoxyalkyl, hydroxyalkoxy,alkylamino, alkylsulfonylamino, alkoxycarbonylamino, aminoalkoxy, oralkoxycarbonylaminoalkoxy;

(j) one or more of the NK3R antagonists disclosed in WO2013/050424, ofgeneral formula II

and pharmaceutically acceptable solvates thereof, wherein

Ar¹ is unsubstituted thiophen-2-yl, unsubstituted phenyl, or4-fluorophenyl;

R¹ is H or methyl;

Ar² is of general formula (i), (ii) or (iii):

-   -   wherein    -   R² is linear or branched C1-C4 alkyl, C1-C2 haloalkyl, linear or        branched C2-C3 alkenyl, C3-C4 cycloalkyl or di(C1-C2        alkyl)amino;    -   X¹ is N or C—R⁶ wherein R⁶ is H, fluoro or C1-C2 alkyl;    -   X² is O or S;    -   X³ is N, or X³ is CH under the condition that X¹ is N and X² is        N—R⁷ wherein R⁷ is linear or branched C1-C3 alkyl or        cyclopropyl;    -   R³ is linear or branched C1-C4 alkyl or C3-C4 cycloalky;    -   X⁴ is N or C—R⁸ wherein R⁸ is H or C1-C2 alkyl;    -   X⁵ is O or S;    -   X⁶ is N, or X⁶ is CH under the condition that X⁴ is N and X⁵ is        N—R⁹ wherein R⁹ is linear or branched C1-C3 alkyl or        cyclopropyl;    -   R⁴ is halo, cyano, methyl, or hydroxyl;    -   R⁵ is H or halo;

(k) one or more of the NK3R antagonists disclosed in WO2014/154895, ofgeneral formula III

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl, nitrile or R³ is        thiophen-2-yl under the condition that R⁵ is not methyl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl;    -   X¹ is N and X² is S or O; or X¹ is S and X² is N;    -   represents a single or a double bound depending on X¹ and X²;    -   stands for the (R)-enantiomer or for the racemate of compound of        formula III;

(l) one or more of the NK3R antagonists disclosed in WO2014/154896;

(m) one or more of the NK3R antagonists disclosed in WO2014/154897.

According to one embodiment, compounds of formula I of group (i), asdisclosed in WO2011/121137, are of formula Ib

and pharmaceutically acceptable salts and solvates thereof, wherein Ar¹,Ar², R₁, R^(1′), R², R^(2′), R³, R^(3′) X¹, X², are as defined informula I.

According to one embodiment, compounds of formula I of group (i), asdisclosed in WO2011/121137, are of formula Ic

and pharmaceutically acceptable salts and solvates thereof, wherein adepicts the bond linking R1 to the piperazine moiety, and Ar¹, Ar², R¹,R^(1′), X¹, and X² are as defined in formula I.

According to one embodiment, compounds of formula I of group (i), asdisclosed in WO2011/121137, are of formula Id-1

and pharmaceutically acceptable salts and solvates thereof, wherein adepicts the bond linking R¹ to the piperazine moiety; and

Ar², R¹, X¹ and X² are as defined in formula I; and

R⁴, R^(4′), R⁵, R^(5′) and R⁶ are independently selected from H, halo,cyano, alkyl, haloalkyl, C3-C6 cycloalkyl, heterocyclyl, aryl,heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino,carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, or R⁵together with R⁴ or R⁶, or R^(5′) together with R^(4′) or R⁶ forms analkylenedioxy group or a haloalkylenedioxy group, or R⁵ together with R⁴or R⁶, or R^(5′) together with R^(4′) or R⁶ forms an aryl moiety fusedto the phenyl group to which they are attached, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl.

According to one embodiment, compounds of formula I of group (i), asdisclosed in WO2011/121137, are of formula Ie-1

and pharmaceutically acceptable salts and solvates thereof, wherein adepicts the bond linking R¹ to the piperazine moiety; and

Ar², R¹, X¹ and X² are as defined in formula I; and

R⁵ and R⁶ are independently selected from H, halo, cyano, alkyl,cyclopropyl, aryl, heteroaryl, each of said aryl and heteroaryl groupsbeing optionally substituted by one or more group(s) selected from halo,alkyl, cyclopropyl, or R⁵ and R⁶ together form a phenyl moiety fused tothe phenyl ring they are attached to.

According to one embodiment, compounds of formula III of group (k), asdisclosed in WO2014/154895, are of formula IIIa

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R¹ is H, F or methyl;    -   R^(1′) is H;    -   R² is H, F, Cl or methoxy;    -   R^(2′) is H or F;    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl, preferably R⁵ is methyl, ethyl,        trifluoromethyl or difluoromethyl, preferably R⁵ is methyl,        ethyl or trifluoromethyl;    -   stands for the (R)-enantiomer or for the racemate of compound of        Formula Ia.

According to one embodiment, compounds of formula III of group (k), asdisclosed in WO2014/154895, are of formula IIIa-1

-   -   and pharmaceutically acceptable solvates thereof, wherein:    -   R³ is H, F, Cl, methyl, trifluoromethyl or nitrile, preferably        R³ is H, F or Cl;    -   R⁴ is methyl, ethyl, n-propyl, hydroxyethyl, methoxyethyl,        trifluoromethyl, difluoromethyl or fluoromethyl, preferably R⁴        is methyl, ethyl, n-propyl or hydroxyethyl;    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl        or 2,2,2-trifluoroethyl, preferably    -   R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,        difluoromethyl or fluoromethyl, preferably R⁵ is methyl, ethyl,        trifluoromethyl or difluoromethyl, preferably R⁵ is methyl,        ethyl or trifluoromethyl;    -   stands for the (R)-enantiomer or for the racemate.

According to one embodiment, compounds of formula III of group (k), asdisclosed in WO2014/154895, are of formula IIIa-1′

and pharmaceutically acceptable solvates thereof, wherein R³, R⁴ andR⁵are as defined in formula IIIa-1.

According to one embodiment, specific compounds of group (i), asdisclosed in WO2011/121137, of group (j), as disclosed in WO2013/050424and of group (k), as disclosed in WO2014/154895 include compounds below:

Cpd n^(o) Structure Chemical name MW i-71

(R)-(4-fluorophenyl)(3-(2-(4- fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone438.5 i-114

(8-methyl-3-(2-phenyloxazol- 4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 468.5 i-144

(R)-(8-methyl-3-(quinolin-2- yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 452.5 i-156

(R)-(3-(2-(2,4- difluorophenyl)thiazol-4-yl)-8- methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 520.6 j-1

(R)-(8-methyl-3-(2- methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 421.53 j-19

(R)-(8-methyl-3-(4- methylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 421.54 k-1

(R)-(3,4-dichlorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 409.29 k-2

(R)-(3-(3-ethyl-1,2,4- thiadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 372.42 k-3

(R)-(4-chlorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 374.85 k-4

(R)-(4-chloro-3- fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 392.84 k-5

(R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 358.39 k-6

(R)-(3-chloro-4- fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 392.84 k-7

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(3,4,5-trifluorophenyl)methanone 394.37 k-8

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4-trifluorophenyl)methanone 394.37 k-9

(R)-(3,4-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 376.38 k-10

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(2,3,4,5-tetrafluorophenyl)methanone 421.36 k-11

(R)-(4-fluorophenyl)(8-(2- hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 388.42 k-12

(4-fluorophenyl)(8-(2- hydroxyethyl)-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 388.42 k-13

(R)-(3-(3-ethyl-1,2,4- oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 356.35 k-14

(4-fluorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone358.39 k-15

(R)-(3-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 358.39 k-16

(R)-(3-chlorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 374.85 k-17

(R)-(3,5-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 376.38 k-18

(R)-(2,4-difluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 376.38 k-19

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(p- tolyl)methanone354.43 k-20

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)(phenyl)methanone 340.4k-21

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-(trifluoromethyl)phenyl) methanone 408.4 k-22

(R)-(8-ethyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 372.42 k-23

(8-ethyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4- fluorophenyl)methanone372.42 k-24

(R)-(4-fluorophenyl)(3-(3- methyl-1,2,4-thiadiazol-5-yl)-8-propyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone386.45 k-25

(R)-(4-fluoro-3- methoxyphenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5- yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 388.42 k-26

(R)-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(o- tolyl)methanone354.43 k-27

(R)-(3-methoxyphenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 370.43 k-28

(R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 342.33 k-29

(R)-4-(8-methyl-3-(3-methyl- 1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine-7- carbonyl)benzonitrile365.41 k-30

(R)-(3-(3-ethyl-1,2,4- oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)(4- (thiophen-2-yl)phenyl)methanone 420.49 k-31

(8-methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(2,3,4,5-tetrafluorophenyl)methanone 412.36 k-32

(3,4-difluorophenyl)(8-methyl- 3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone376.38 k-33

(8-methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(2,3,4-trifluorophenyl)methanone 394.37 k-34

(8-methyl-3-(3-methyl-1,2,4- thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(3,4,5-trifluorophenyl)methanone 394.37 k-35

(3-chloro-4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 392.84 k-36

(4-chloro-3-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 392.84 k-37

(4-chlorophenyl)(8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone374.85 k-38

(3,4-dichlorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 409.29 k-39

(3-(3-ethyl-1,2,4-thiadiazol-5- yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4- fluorophenyl)methanone372.42 k-40

(3-(3-ethyl-1,2,4-oxadiazol-5- yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4- fluorophenyl)methanone356.35 k-41

(R)-(4-fluorophenyl)(8- methyl-3-(3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl)-5,6- dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 412.36 k-42

(R)-(3-(3-(difluoromethyl)- 1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-fluorophenyl)methanone 394.37 k-43

(R)-(3-(3-(1,1-difluoroethyl)- 1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4-fluorophenyl)methanone 392.34 k-44

(R)-(4-fluorophenyl)(8- methyl-3-(3-(2,2,2- trifluoroethyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 410.33 k-45

((8R)-3-(3-(1-fluoroethyl)- 1,2,4-oxadiazol-5-yl)-8- methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)(4- fluorophenyl)methanone374.34

and pharmaceutically acceptable solvates thereof.

In Table 1, the term “Cpd” means compound. The compounds were namedusing ChemBioDraw® Ultra version 12.0 (PerkinElmer).

According to a specific embodiment, the NK3R antagonist is k-5.

According to a specific embodiment, the NK3R antagonist is not SB222200.

Formulations Comprising NK3R Antagonists

The present invention also relates to formulations comprising NK3Rantagonists for use in the therapeutic or cosmetic treatment of excessbody fat and/or of excess body weight, preferably in the therapeutictreatment of excess body fat and/or prevention of body fat gain.

In the case of the therapeutic treatment of excess body fat and/or ofexcess body weight, preferably in the therapeutic treatment of excessbody fat and/or prevention of body fat gain, the formulation is apharmaceutical composition. According to one embodiment, thepharmaceutical composition comprises an NK3R antagonist as describedabove and at least one pharmaceutically acceptable vehicle, such as forexample at least one carrier, diluent, excipient and/or adjuvant. Asindicated above, the NK3R antagonist may be a stereoisomer, a mixture ofstereoisomers, a prodrug, a pharmaceutically acceptable salt, a hydrate,a solvate, an acid salt hydrate, an N-oxide or an isomorphic crystallineform.

In the case of the cosmetic treatment of excess body fat and/or ofexcess body weight, the formulation is a cosmetic composition. Accordingto one embodiment, the cosmetic composition comprises an NK3R antagonistas described above and at least one physiologically acceptable carrier,diluent, excipient and/or adjuvant. As indicated above, the NK3Rantagonist may be a stereoisomer, a mixture of stereoisomers, a prodrug,a pharmaceutically acceptable salt, a hydrate, a solvate, an acid salthydrate, an N-oxide or an isomorphic crystalline form.

The formulation of the NK3R antagonist for use according to the presentinvention as well as its amount depend on the therapeutic or cosmeticpurpose of the treatment, and will be clear to the skilled person.

By means of non-limiting examples, such formulations may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, for transdermal administration such as forexample by a skin patch, by an implant, by a suppository, etc. Suchsuitable administration forms—which may be solid, semi-solid or liquid,depending on the manner of administration—as well as methods andcarriers, diluents and excipients for use in the preparation thereof,will be clear to the skilled person; reference is made for example tothe latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used in suchformulations, such as lubricating agents, wetting agents, emulsifyingand suspending agents, dispersing agents, desintegrants, bulking agents,fillers, preserving agents, sweetening agents, flavoring agents, flowregulators, release agents, etc. The compositions may also be formulatedso as to provide rapid, sustained or delayed release of the activecompound(s) contained therein.

According to a specific embodiment, the formulation is in a formsuitable for oral administration. According to a preferred embodiment,the formulation is under the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols, soft and hard gelatin capsules, or drops. According to aspecific embodiment, the formulation is under the form of tablets.According to another specific embodiment, the formulation is under theform of soft or hard gelatin capsules. According to another specificembodiment, the formulation is under the form of loose powder,preferably contained in sachets.

The formulations of the invention are preferably in a unit dosage form,and may be suitably packaged, for example in a box, blister, vial,bottle, sachet, ampoule or in any other suitable single-dose ormulti-dose holder or container (which may be properly labelled);optionally with one or more leaflets containing product informationand/or instructions for use. Generally, such unit dosages will containbetween 0.05 and 1000 mg, and usually between 1 and 500 mg, preferablybetween 2 and 150 mg of NK3R antagonist, e.g. about 2, 4, 8, 16, 32, 64or 128 mg per unit dosage. According to another embodiment, such unitdosages will contain between 0.05 and 1000 mg, and usually between 1 and500 mg, preferably between 2 and 400 mg, preferably between 2 and 200 mgof NK3R antagonist per unit dosage.

Depending on the therapeutic or cosmetic use and the route ofadministration, the NK3R antagonist will usually be administered between0.001 and 10 mg per kilogram body weight, more often between 0.01 and 4mg per kilogram body weight, preferably between 0.02 and 1.5 mg perkilogram body weight, for example about 0.02, 0.04, 0.08, 0.16, 0.32,0.64 or 1.28 mg, per kilogram body weight of the patient per day, whichmay be administered as a single daily dose, divided over one or moredaily doses, or essentially continuously, e.g. using a drip infusion.According to another embodiment, the NK3R antagonist will usually beadministered between 0.001 and 10 mg per kilogram body weight, moreoften between 0.01 and 7 mg per kilogram body weight, preferably between0.03 and 3.5 mg per kilogram body weight of the patient per day, whichmay be administered as a single daily dose, divided over one or moredaily doses, or essentially continuously, e.g. using a drip infusion.

According to one embodiment, less than 55 mg of the NK3R antagonist isadministered to the patient, preferably less than 40 mg, more preferablyless than 30 mg, even more preferably less than 20 mg. According toanother embodiment, more than 55 mg of the NK3R antagonist isadministered to the patient, preferably from 55 to 200 mg, morepreferably from 60 to 180 mg.

According to one embodiment, the NK3R antagonists for use in thetherapeutic or cosmetic methods of the invention can be administered incombination with other therapeutic agents and/or active ingredients.

In one embodiment of the invention, the NK3R antagonist may beadministered in combination with other additional active substances orcompounds, provided said additional active substances or compounds arenot detrimental to the therapeutic or cosmetic activity of the NK3Rantagonist for use of the invention.

Advantageously, an additional active substance stimulates the weightloss or the body fat reduction and/or contributes to the prevention ofweight gain or of body fat development.

Any additional compound with a nutritional interest and/or stimulatingweight loss or body fat reduction, or preventing fat gain, may also beadded to the NK3R antagonist for use of the invention in apharmaceutical or cosmetic form. It may be for example, vitamins,mineral salts, essential amino acids, essential fatty acids,oligo-elements, various natural extracts, fibers, antioxidants,flavonoids.

In the case of combination regimen, the NK3R antagonist and other activesubstances may be administered in terms of dosage forms eitherseparately or in conjunction with each other, and in terms of their timeof administration, either serially or simultaneously. Thus, theadministration of one component agent may be prior to, concurrent with,or subsequent to the administration of the other component agent(s).

Uses

The present invention relates to the use of NK3R antagonists andformulations thereof as described above for the therapeutic or cosmetictreatment of excess body fat and/or of excess body weight, preferably inthe therapeutic treatment of excess body fat and/or prevention of bodyfat gain.

“Therapeutic treatment” should be distinguished from “cosmetictreatment”. When not otherwise specified, “treatment” should beunderstood as “therapeutic treatment”. The same applies to related terms“treat” and “treating”.

Therapeutic Use

In the context of therapeutic treatment, “excess of body fat and/or ofexcess body weight” in a patient should be understood as “pathologicalexcess of body fat and/or of excess body weight”, i.e. referring to anexcess of body fat and/or of excess body weight associated with agrowing burden of disease (typically glucose metabolism disorders,insulin resistance, metabolic syndrome, diabetes or vascular disorders);as it is especially the case with abdominal adiposity. Moreover, in thiscontext, “prevention of body fat gain in a patient” should be understoodas referring to the prevention of body fat gain wherein if the fat gainhad occurred, it would occur an excess of body fat associated with agrowing burden of disease (typically glucose metabolism disorders,insulin resistance, metabolic syndrome, diabetes or vascular disorders);as it is especially the case with abdominal adiposity. The term“overweight” is taken to mean the medical condition in which excess bodyfat has accumulated to the extent that it may have an adverse effect onhealth, leading to reduced life expectancy and/or increased healthproblems. Body mass index (BMI), a measurement which compares weight andheight, defines people as “overweight” if their BMI is between 25 and 30kg/m², and “obese” when it is greater than 30 kg/m². Therefore,overweight patients are not obese.

In a general meaning, “therapeutic treatment” refers to treatment,prophylactic or preventive measures and deferment of the disease onset;wherein the object is to delay, prevent or slow down (lessen) thetargeted pathologic condition or disorder, in a patient. The term“patient” refers to a warm-blooded animal, more preferably a human,who/which is awaiting or receiving medical care or is or will be theobject of a medical procedure, or monitored for the development of adisease. Patients include those already with the disorder as well asthose prone to have the disorder or those in whom the disorder is to beprevented or delayed.

In one embodiment, “therapeutic treatment” means accomplishing one ormore of the following in a patient that is suffering from pathologicalexcess of body fat and/or of excess body weight: (a) reducing theseverity of excess body fat and/or of excess body weight; (b) limitingor preventing development of excess body fat and/or of excess bodyweight; (c) inhibiting worsening of excess body fat and/or of excessbody weight; and (d) limiting or preventing recurrence of excess bodyfat and/or of excess body weight in patients that previously had excessbody fat and/or of excess body weight.

In one embodiment, a patient is successfully “treated” if, afterreceiving a therapeutic amount of the active agent, the patient showsobservable and/or measurable stabilization or reduction of body weightand/or body fat mass; and/or relief to some extent of one or more of thesymptoms associated with excess body weight and/or excess body fat;reduced morbidity and mortality, and improvement in quality of lifeissues. The above parameters for assessing successful treatment andimprovement in the disease are readily measurable by routine proceduresfamiliar to a skilled artisan.

According to one embodiment, “treating excess body weight” means thatthe administration of an NK3R antagonist, such as defined herein, andwith a dosage determined by the person skilled in the art, makes itpossible to reduce the weight of the treated patients. Such NK3Rantagonist also enables to prevent weight gain and/or to stabilize aweight as low as possible, and/or to delay the development of excessbody weight, especially in patient having a risk of developing excessbody weight.

According to one embodiment, “treating excess body fat” means that theadministration of an NK3R antagonist, such as defined herein, and with adosage determined by the person skilled in the art, makes it possible toreduce the body fat of the treated patients. Such NK3R antagonist alsoenables to prevent the accumulation of body fat and/or to maintain abody fat as reduced as possible, and/or to delay the accumulation ofbody fat, especially in patient having a risk of developing excess bodyweight and/or of developing an excess body fat of pathological nature(i.e. associated with a growing burden of disease); as is often the casewith abdominal adiposity.

According to one embodiment, “treating excess of body fat and/or ofexcess body weight” refers to any one or more of treating, preventing,arresting and reducing weight-gain, whereby at least one or more of thefollowing is achieved:

-   -   decrease in body fat and/or body weight, preferably decrease in        body fat;    -   prevention of weight gain and/or cessation of weight gain;    -   decrease or maintenance of plasma triglyceride levels;    -   improvement in leptin resistance;    -   reduction in hyperglycemia and/or decrease in incidence or        severity of diabetes;    -   reduction in hyperlipidaemia and/or hypertriglyceridemia;    -   decrease in food intake;    -   improvement in at least one condition associated with weight        gain including a cardiovascular disorder, a sleep disorder, a        metabolic condition, a diabetes-related condition;    -   at least partial improvement (e.g., termination of or reduction        in occurrence) of a condition selected from binge eating        disorder, night eating syndrome, obsessive eating, compulsive        eating or bulimia.

The present invention thus relates to a NK3R antagonist for use in thetreatment of excess body weight and/or excess body fat, especially thetreatment of excess body fat and/or the prevention of body fat gain.According to the one embodiment, the invention relates to a NK3Rantagonist for use in the therapeutic treatment of pathological excessbody weight and/or excess body fat. According to the one embodiment, theinvention relates to a pharmaceutical composition comprising a NK3Rantagonist for use in the therapeutic treatment of pathological excessbody weight and/or excess body fat.

According to one embodiment, the invention relates to the use of a NK3Rantagonist in the manufacture of a medicament for the treatment ofexcess body weight and/or excess body fat. According to a specificembodiment, the invention relates to the use of a NK3R antagonist in themanufacture of a medicament for the treatment of excess body weightand/or excess body fat, comprising the manufacture of tablets comprisingthe NK3R antagonist. According to a specific embodiment, the inventionrelates to the use of a NK3R antagonist in the manufacture of amedicament for the treatment of excess body weight and/or excess bodyfat, comprising the manufacture of capsules comprising the NK3Rantagonist. According to a specific embodiment, the invention relates tothe use of a NK3R antagonist in the manufacture of a medicament for thetreatment of excess body weight and/or excess body fat, comprising themanufacture of sachets of loose powder comprising the NK3R antagonist.

According to one embodiment, the invention relates to a method oftreatment of excess body weight and/or excess body fat, comprising theadministration of an effective amount of NK3R antagonist to a patientsuffering from excess body weight and/or excess body fat, and optionalrenewal of said administration until the desired therapeutic effect isobtained.

According to one embodiment, the invention also relates to a method oftreatment of excess body weight and/or excess body fat, comprising theadministration of an effective amount of a pharmaceutical compositioncomprising a NK3R antagonist, to a patient suffering from excess bodyweight and/or excess body fat, and optional renewal of saidadministration until the desired therapeutic effect is obtained.

The term “therapeutically effective amount” (or more simply an“effective amount”) as used herein means the amount of active agent(e.g. NK3R antagonist) that is effective for treating pathologicalexcess body fat and/or of excess body weight. The effective amount mayvary from patient to patient, depending upon the age, the patient's sizeand health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombinations of therapeutics selected for administration.

Especially, the invention relates to the treatment and/or prevention ofabdominal fat accumulation, the impact of which is highly worrying interms of morbidity and mortality.

In the treatment of the invention, the body fat loss occurs without anyloss of the lean body mass (i.e. with no muscular atrophy), the weightloss is thus essentially associated with a targeted body fat loss.

In the treatment of the invention, the body fat loss occurs without anyloss of bone mineral density or bone mineral content, the weight loss isthus essentially associated with a targeted body fat loss.

In the treatment of the invention, the body fat loss occurs without anyloss of bone mineral density or bone mineral content and without anyloss of the lean body mass (i.e. with no muscular atrophy), the weightloss is thus essentially associated with a targeted body fat loss.

In a particular embodiment, the method of treatment of the invention maycomprise the administration of at least one additional active substancefor the same therapeutic indication and/or for complementaryindications. In a preferred embodiment, the NK3R antagonist is the onlysubstance administered as active substance for treating excess bodyweight and/or excess body fat.

The therapeutic use of NK3R antagonists according to the presentinvention is intended for patients that are suffering from pathologicalexcess of body fat and/or of excess body weight, especially for patientsthat are suffering from pathological excess of body fat. The therapeuticuse of NK3R antagonists according to the present invention is alsointended for patients that are prone to suffer from pathological excessof body fat and/or of excess body weight, especially for patients thatare prone to suffer from pathological excess of body fat. According to aspecific embodiment, in the present invention, patients do not sufferfrom obesity.

The therapeutic use of NK3R antagonists according to the presentinvention for the treatment of excess body fat and/or the prevention ofbody fat gain, is intended for patients that are leptin-sensitivepatients, preferably leptin sensitive women patients. In this context,according to one embodiment, “leptin-sensitive patients” encompass (i)patients in whom the circulating leptin levels are low (hypoleptinemicstate) and (ii) patients in whom the circulating leptin levels arenormal but in any case the patients remain in a leptin-sensitive state.In this context, according to a specific embodiment, “leptin-sensitivepatients” refers to patients in which a variation of circulating leptinlevels has an effect on body fat mass.

According to one embodiment, patients are individuals suffering fromhormonal imbalance. According to a specific embodiment, patients areindividuals at risk of weight gain due to an anticipated decrease in thelevels of the sex hormones (namely, androgens in the case of men andestrogens in the case of women). Specific examples include:

-   -   women subjected to estrogen-lowering therapies, for example in        the context of the treatment of breast, cervical, uterine        cancers; or for the treatment of women's health disorders such        as endometriosis, uterine fibroids, heavy menstrual bleeding and        polycystic ovary syndrome (PCOS);    -   women experiencing natural, age-related decreases in estrogens        as occurring during peri-menopause and post-menopause;    -   men subjected to androgen-lowering therapies, for example in the        context of the treatment of prostate-cancer or benign prostatic        hyperplasia (BPH);    -   men experiencing natural, age-related decreases in circulating        testosterone.

According to a specific embodiment, patients are women, especially womenthat undergo changes in ovarian hormone levels.

According to a specific embodiment, patients are women subjected toestrogen-lowering therapies. According to a specific embodiment,patients are women experiencing natural, age-related decreases inestrogens.

According to a specific embodiment, patients are men subjected toandrogen-lowering therapies. According to a specific embodiment,patients are men experiencing natural, age-related decreases incirculating testosterone.

According to one embodiment, patients are individuals suffering fromgenetic susceptibility to excess body weight.

According to one embodiment, patients are individuals where anadipose-specific decrease in weight is deemed to be of therapeuticbenefit. Specific examples include overweight individuals; individualsreceiving medical treatments that are accompanied with weight gaincomprising but not limited to hormonal treatment as well as steroids,pain or antipsychotic medications; individuals having inappropriateeating behaviors.

According to one embodiment, patients are overweight individuals.According to a specific embodiment, patients are not obese. According toone embodiment, patients are individuals receiving medical treatmentswhich can cause weight gain. According to one embodiment, patients areindividuals having inappropriate eating behaviors.

The present invention also relates to the use of NK3R antagonists andformulations thereof as described above for increasing circulatingleptin levels in a patient in need thereof. According to one embodiment,the invention relates to a NK3R antagonist for use in increasingcirculating leptin levels in a patient. According to one embodiment, theinvention relates to the use of a NK3R antagonist for the manufacture ofa medicament for increasing circulating leptin levels in a patient. Theinvention also provides a method for increasing circulating leptinlevels in a patient comprising the administration of an NK3R antagonistto a patient in need thereof.

The present invention also relates to the use of NK3R antagonists andformulations thereof as described above for the treatment ofleptin-related diseases. According to one embodiment, the inventionrelates to a NK3R antagonist for use in the treatment of aleptin-related disease. According to one embodiment, the inventionrelates to the use of a NK3R antagonist for the manufacture of amedicament for treating and/or preventing leptin-related diseases. Theinvention also provides a method of treatment of a leptin-relateddisease comprising the administration of an NK3R antagonist to a patientin need thereof.

According to one embodiment, a disease is related to leptin whencirculating leptin levels are lower compared to healthy subjects. Thedetermination of the circulating leptin levels, especially in bloodand/or plasma, may be performed by means known by those skilled in theart, such as for example by enzyme-linked immunosorbent assay (ELISA).

According to an embodiment, a disease is related to leptin when leptinor leptin gene is altered in its structure and thus in its function orwhen the leptin receptor or leptin receptor gene is altered in itsstructure and thus in its function, compared to healthy subjects.

According to an embodiment, a “leptin-related disease” is a diseasewherein increasing leptin levels may improve or normalize most ofpatient phenotypes and so is beneficial for the patient. Leptin-relateddiseases encompass (i) diseases where the circulating leptin levels arelow (hypoleptinemic state) and (ii) diseases where the circulatingleptin levels are normal but in any case the patients affected by suchdiseases remain in a leptin-sensitive state.

In one embodiment, the leptin-related disease is selected from metabolicdisorders such as diabetes (especially type 1 diabetes), cardiovasculardiseases or metabolic syndrome; lipid regulation disorders such aslipodystrophy, including congenital and acquired lipodystrophy,dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholicsteatohepatitis (NASH) or hyperlipidemia; Congenital Leptin Deficiency(CLD); hypothalamic amenorrhea, including exercise-induced hypothalamicamenorrhea; Rabson-Mendenhall syndrome; osteoporosis.

According to one embodiment, the invention relates to the use of a NK3Rantagonist as a leptin replacement therapy in any leptin-sensitivestate. In one embodiment, the invention relates to the use of a NK3Rantagonist as a substitution product of recombinant leptin, preferablyas a substitution product of recombinant methionyl human leptin, morepreferably as a substitution product of metreleptin.

Cosmetic Use

The present invention also relates to the use of NK3R antagonists orformulations thereof for the cosmetic treatment of excess body fatand/or of excess body weight in a subject.

In the cosmetic context, “excess of body fat and/or of excess bodyweight” in a subject should be understood as “unaesthetic excess of bodyfat and/or of excess body weigh”, i.e. referring to an excess bodyweight or fat accumulation which is not associated with pathologicalconditions or a growing burden of disease. Such excess body weight orbody fat typically exists as cellulite and is preferably distributedaccording to a gynoid pattern.

The term “subject” refers to a warm-blooded animal, more preferably ahuman, who/which is in good health, with a normal corpulence, i.e.having a BMI from 18.5 to 25 kg/m², the excess body weight or fataccumulation of whom is not associated with no pathological conditionsor a growing burden of disease (typically glucose metabolism disorders,insulin resistance, metabolic syndrome, diabetes or vascular disorders).

The “cosmetic treatment” is intended to provide an aesthetic/cosmeticeffect in subjects, by improving the bodily appearance throughstimulating the loss of body weight and/or of body fat. It enablessubjects to stabilize weight and to stay thin without localized fatdeposits. The cosmetic method according to the invention is especiallysuited to the reduction of cellulite, in particular on hips and buttock.

The present invention thus relates to a cosmetic treatment method forimproving the bodily appearance by stimulating the loss of body weightand/or of body fat in a subject, comprising the administration to saidsubject of a NK-3 receptor antagonist as defined above, and optionallythe renewal of said administration until the expected cosmetic effect isobtained.

According to one embodiment, the present invention also relates to acosmetic treatment method for improving the bodily appearance bystimulating the loss of body weight and/or of body fat in a subject,comprising the administration to said subject of cosmetic compositioncomprising a NK-3 receptor antagonist as defined above, and optionallythe renewal of said administration until the expected cosmetic effect isobtained.

The cosmetic method of the invention is non-therapeutic.

According to one embodiment, the cosmetic method of the invention isaimed at subjects which are individuals being in good health.Especially, the subjects have a normal corpulence, according to the WHOstandards, and thus being not obese.

Advantageously, in the cosmetic method of the invention, the body fatloss occurs without any loss of the lean body mass (i.e. with nomuscular atrophy), the weight loss is thus essentially associated with atargeted body fat loss.

According to a specific embodiment, in the cosmetic method of theinvention, the NK3R antagonist is adapted to oral administration and isintended to be taken as a food supplement. It may comprise anyadditional compound with a nutritional interest and/or stimulatingweight loss or body fat reduction. It could comprise, for example,vitamins, mineral salts, essential amino acids, essential fatty acids,oligo-elements, various plant extracts, fibers, antioxidants,flavonoids. Natural components may also be mentioned which haveanorectic properties.

In a particular embodiment, the NK3R antagonist is the only substanceadministered as active substance for slimming the figure and/or reducingor restraining localized fat accumulations or lipodystrophia, and/or forstimulating the loss of excess body weight and/or of cellulite, and/orfor limiting the accumulation thereof. In another embodiment, the NK3Rantagonist is the only substance administered as active substance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a histogram showing the %Fat/Total Mass ratio in the pre-dosephase (left column) versus final week (week-13) of the dosing phase(right column) for each group (vehicle-control group versus treatedgroups with 10 and 50 mg/kg of compound k-5). Data are presented asmean±SEM; N=4-6/group, stats by 2-way ANOVA, Bonferroni's MCT.

FIG. 2 is a graph showing the plasma leptin level along treatment forthe vehicle-control group versus treated group with 50 mg/kg of compoundk-5 (*: p<0.05, 2-way ANOVA & Sidak's MCT).

FIG. 3 is a graph showing the percentage of body weight increase alongtreatment for the vehicle-control group versus treated group with 50mg/kg of compound k-5.

FIG. 4 is a diagram showing plasma leptin level in the pre-dose phaseversus 4 h after final dose, for each group (placebo group versustreated groups with 20, 60 and 180 mg of compound k-5) (*p<0.05; pairedt-test).

FIG. 5 is a histogram showing plasma leptin level in baseline estrouscycle (left column) versus treatment estrous cycle (right column) foreach group (vehicle-control group versus treated group with 10 mg/Kg ofcompound k-5) (*p<0.05, paired t-test).

EXAMPLES

The present invention will be better understood with reference to thefollowing examples.

Example 1 Decrease of % Fat/Total Mass in Monkeys

The cynomolgus monkey was selected as a relevant species because of thesimilarity of nonhuman primates (NHP) to humans. The route ofadministration is oral consistent with the intended route in humans.

Sexually-mature (age range of ˜4 years at pre-dose), purpose-bredcynomolgus monkeys (Macaca fascicularis) of Asian origin were used.Sexual maturity was proven by recording of at least two menstrualbleedings (with 20-to-50 days between menstruations) prior to entry intothe study.

NHPs were maintained on a standard lab diet of twice-daily offerings ofcommercial pellets for primates supplemented with fresh fruit and bread.Dietary and environmental enrichment were also provided through thestudy duration. Animals were housed in a climate (19-25° C.) andhumidity (40-70%) controlled environment with artificial lightingcontrolled automatically to give a cycle of 12 hours light and 12 hoursdark.

NHPs were divided into three treatment groups: vehicle control (N=6) andcompound k-5 Dose Groups of 10 mg/kg (N=4) and 50 mg/kg (N=6),respectively. All NHPs were dosed once daily (morning) by oral gavageover the 13 week treatment period of the study. The dose vehicle was0.5% methylcellulose (Methocel® from Colorcon) in water.

All NHPs were subjected to a body weight measurement and DEXA scan(Dual-energy X-ray absorptiometry, Hologic Dexa QDR® 4000) in thepre-dose phase and in the final week (week-13) of the dosing phase. Themeasurements were made under ketamine anesthesia with dorbene andantisedan.

The whole body was scanned by DEXA for measurement of lean mass, bonemineral density, bone mineral content and fat mass.

All NHPs were subjected to leptin levels measurements. Blood sampleswere collected at 08h00 in the morning from overnight-fasted animals onDay-2 prior to dosing (‘pre-dose’), 24 h after the initial dosing, onday 52 of dosing and on day 86 of dosing. Serum samples were derivedfrom these blood samples and stored frozen (−20° C.) until analysis.Leptin concentrations in these serum samples were determined by ELISAassay (Monkey Kit: MyBiosource Cat. N° MBS705354) based upon linearregression analysis against a standard curve.

Effect on body weight: A mean weight gain of about 12% was observed invehicle-treated monkeys over the course of the dosing phase of the study(FIG. 3). In comparison, there was no significant change in mean weightfor the k-5 treated group over the course of the dosing phase of thestudy.

Effects on body composition: There were no significant changes in leanmass, nor bone mineral density not bone mineral content at anymeasurement, for any group, over the course of the study. DEXA analysisrevealed that % fat/total mass increased in the vehicle group over the13-week study course, as is often observed as NHPs are confined tostudy. In contrast, no significant change in % fat/total mass wasobserved in any of the compound k-5 dose groups over the 13-weektreatment period, as presented in FIG. 1. A statistically-significantdifference was determined between the vehicle-treated and 50mg/kg-treated groups where N values were 6 subjects/group. In total,these data demonstrate that treatment with compound k-5 preventsadiposity gain in monkeys while not decreasing lean mass.

Effects on leptin: FIG. 2 illustrates that compound k-5 treatmentsignificantly increases serum leptin levels 24-hours after initialdosing relative to (a) pre-dose levels within the same group and (b)time-matched levels within the vehicle-treated group. Also, the figureillustrates that serum leptin levels were persistently higher in thek-5-treated group relative to the vehicle-treated group over theduration of dosing.

Study conclusions: Sexually-mature, female monkeys treated withcompounds of the invention have decreased weight gain relative tovehicle treated controls. This difference in weight gain is due entirelyto a drug-related reduction in % fat mass relative to vehicle controlsand not due to changes in bone or muscle density. Moreover, thisdecrease in % fat mass, relative to vehicle group, correlates with asignificant increase in circulating leptin concentrations in response totreatment.

Example 2 Decrease of Total Body Weight in Healthy Women

Multiple Ascending Dose Administration in Healthy Women

Three Panels A, B, and C, each consisting of 6 healthy women, wererandomized to receive different dose level of compound k-5. In those 3panels, compound k-5 is administered for 21 consecutive days.

Subjects were residential from the day before first dosing (D-1) untilDay 24 (=72 hours after the last dose intake on Day 21). Weeklynon-residential visits were organized on Day 28, Day 35 (±1 day) and afollow-up visit on Day 42 (±2 days). Ascending multiple doses ofcompound k-5 were administered in a once-daily regimen for 21consecutive days. The suggested dose levels were: 20 mg, 60 mg and 180mg based on previous studies. Subjects received the trial medication ina q.d. regimen and after a light breakfast.

Main Criteria for Subject Inclusion

Subjects were recruited on the basis of their medical history and healthstatus. Especially, subjects meeting all of the following criteria wereeligible to participate in this study:

1) Premenopausal females between 18 and 45 years of age inclusive.

2) Healthy with no clinically significant abnormalities as determined bymedical history, physical examination, blood chemistry assessments,hematologic assessments, coagulation and urinalysis, measurement ofvital signs, and ECG. Isolated out-of-range values judged by thephysician to be of no clinical significance were allowed. Thisdetermination had to be recorded in the subject's source documents.

3) Had a body weight in the range of 50 to 100 kg inclusive.

4) Agreed to abstain from alcohol intake 24 hours before administrationof study compound, during the period of the study and 24 hours prior toall other clinic visits.

5) Agreed not to use prescription medications within 14 days prior tostudy compound administration and through the duration of the study,unless approved by the Investigator and Sponsor medical monitor.

6) Agreed not to use over-the-counter (OTC) medications (includingcorticosteroids, aspirin, decongestants, antihistamines, and othernon-steroidal anti-inflammatory drug [NSAIDs]), and herbal medication(including herbal tea, St. John's Wort), within 14 days prior to studycompound administration through the final follow-up visit, unlessapproved by the investigator and Sponsor medical monitor. Occasional useof paracetamol at recommended doses was allowed.

7) Subjects had to have signed an informed consent document indicatingthat they understood the purpose of and procedures required for thestudy and were willing to participate in the study.

8) Willing/able to adhere to the study visit schedule and otherrequirements, prohibitions and restrictions specified in this protocol.

Weight Measurement

The weight was measured at screening, which took place between 28 and 2days before start of dosing (D-28 to D-2), and at the end-of-study visit(D42, i.e. 21 days after cessation of study compound intake).

Results

A two-tailed T-test for paired samples was used to explore thedifference between the screening and post-study values for weight. Meanvalues per dose group are tabulated in the following table:

Weight Pre vs Pre vs Screen- Weight Post Post ing D 42 DifferenceDifference Matching Dose group (kg) (kg) (kg) (%) p-value Cpd k-5 20 mg58.2 58.0 −0.13 −0.23% 0.70 Cpd k-5 60 mg 73.3 71.9 −1.38 −1.92% 0.15Cpd k-5 180 mg 69.0 66.9 −2.10 −3.14% <0.02

Based on these results it can be concluded that a dose-dependent trendexists towards weight lowering with increasing doses of compound k-5,reaching a significance level of 0.02 in the highest dose group testedin healthy women.

Example 3 Decrease of Body Weight in Healthy Women with NormalCorpulence

Healthy women with normal corpulence, i.e. having a BMI ranging from18.5 to 25 kg/m², received 60 mg of compound k-5 for 21 consecutivedays.

The weight was measured at screening which took place between 28 and 2days before start of dosing (D-28 to D-2), as well as on the follow-upvisit planned on D42 (21 days after cessation of study compound intake).

Weight and BMI before and after dosing are presented below:

Weight Weight Height Screening D42 Difference Difference BMI Subject(cm) (kg) (kg) (kg) (%) screening BMI D42 1 173 66.4 64.2 −2.2 −3.43%22.18 21.45 2 163 63 61 −2 −3.28% 23.71 22.95 3 178 68.3 67.8 −0.5−0.74% 21.55 21.39

These results evidence that the use of a NK3R antagonist enableslowering weight in healthy women.

Example 4 Decrease of Body Weight in Overweight Women

Overweight women, i.e. having a BMI ranging from 25 to 30 kg/m²,received 180 mg of compound k-5 for 21 consecutive days.

The weight was measured at screening which took place between 28 and 2days before start of dosing (D-28 to D-2), as well as on the follow-upvisit planned on D42 (21 days after cessation of study compound intake).

Weight and BMI before and after dosing are presented below:

Weight Weight Height Screening D42 Difference Difference BMI Subject(cm) (kg) (kg) (kg) (%) screening BMI D42 4 156 68 65.2 −2.8 −4.29%27.94 26.79 5 160 71.2 67 −4.2 −6.27% 27.81 26.17 6 179 87 84 −3 −3.57%27.15 26.21

These results evidence that the use of a NK3R antagonist enableslowering weight in overweight women.

Example 5 Effect on Plasma Leptin Level in Women

This was a randomized, double-blind, placebo-controlled study. Allsubjects provided written informed consent prior to screening for studyeligibility. Healthy female volunteers aged 20-45 years with a body massindex of 19-30 kg/m² were included. Participants needed to be in goodphysical health including the presence of a regular ovulatory menstrualcycle and the discontinuation of all hormonal contraceptive methods atleast 3 months prior to screening. Three panels of 8 non-obese femalevolunteers (median BMI of each panel: 22.3, 23.4, 25.2 kg/m²) each wereadministered capsules of compound k-5 or matching placebo in a 6:2 ratiofor 21 days. Subjects received the study medication in a once dailyregimen after a light standardized breakfast. The participants in thesepanels were synchronized for their menstrual cycle; i.e. the initiationof dosing was always on Day3 ±2 of the menstrual cycle. The dose levelsinvestigated were 20, 60 and 180 mg of compound k-5. Blood samples werecollected on the day prior to dosing as well as on Day 21 (the final dayof dosing) and plasma fractions were retained and stored frozen (−20°C.) until analysis. Leptin concentrations in these plasma samples weredetermined by ELISA assay (Human Leptin Kit: R&D Systems, Cat. N° DLP00)based upon linear regression analysis against a standard curve.

Effects on Leptin: FIG. 4 illustrates that compound k-5 treatmentsignificantly (*p<0.05; paired t-test) increases serum leptin levels inwomen at all dose levels following 21 days of treatment relative topre-dose levels. In comparison, placebo treatment had no significanteffect on plasma leptin levels.

Study Conclusion: Compound k-5 increases circulating leptin levels innon-obese, premenopausal women. As leptin is a hormone known to haveeffects on weight gain and adiposity, these results may be relevant to %fat density relative to overall body composition, analogous to the datapresented above for female, non-human primates (example 1).

Example 6 Effect on Plasma Leptin Level in Female Rats over the EstrousCycle

Rats do not have a menstrual cycle, but rather an estrous cycle that canbe clearly defined by peak estrogen levels (precluding ovulation) thatoccurs regularly over a period of ˜4 days.

Daily plasma samples were collected each morning from sexually-maturefemale rats and analyzed for peak estrogen levels (coincident withproestrus) in order to define the timing of the estrous cycle forindividual rats.

Next, rats were dosed orally BID (i.e. twice a day) with vehicle (0.5%methylcellulose) over a 4-day ‘baseline’ estrous cycle. Plasma sampleswere collected daily, each morning, and stored frozen prior to analysisfor leptin.

Then, the rats were separated into two groups treated with eithercompound k-5 10mg/kg, oral BID, or with vehicle over the 4-day‘treatment’ estrous cycle. Plasma samples were collected daily, eachmorning, and stored frozen prior to analysis for leptin.

In a single experiment, plasma samples collected daily during both the‘baseline’ and ‘treatment’ cycles were analyzed in a common experimentby ELISA assay based upon linear regression analysis against a standardcurve. Leptin levels over the 4-day estrous cycle were calculated forindividual rats by determination of AUC (area-under-the-curve) usingcredited data analysis software (GraphPad Prism).

Effects on Leptin: FIG. 5 illustrates that compound k-5 treatmentsignificantly (*p<0.05; paired t-test) increases plasma leptin levels infemale rats over the 4-day estrous cycle compared to when the same ratswere treated with vehicle in the ‘baseline’ cycle.

Study Conclusion: Compound k-5 treatment increases circulating leptinlevels in non-obese, sexually-mature female rats over the estrous cycle.As leptin is a hormone known to have effects on weight gain andadiposity, this finding may be relevant to % fat density relative tooverall body composition, analogous to the data presented above forfemale, non-human primates (example 1) and in women (example 5).

1. A method of treatment of a leptin-related disease comprising theadministration of an NK-3 receptor antagonist to a patient in needthereof, wherein the NK-3 receptor antagonist is of general formula III:

or a pharmaceutically acceptable solvate thereof, wherein: R¹ is H, F ormethyl; R^(1′) is H; R² is H, F, Cl or methoxy; R^(2′) is H or F; R³ isH, F, Cl, methyl, trifluoromethyl, nitrile or R³ is thiophen-2-yl underthe condition that R⁵ is not methyl; R⁴ is methyl, ethyl, n-propyl,hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl orfluoromethyl; R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or2,2,2-trifluoroethyl; X¹ is N and X² is S or O; or X¹ is S and X² is N;

represents a single or a double bound depending on X¹ and X²; and

stands for the (R)-enantiomer or for the racemate compound of formulaIII.
 2. The method according to claim 1, wherein the leptin-relateddisease is selected from the group consisting of metabolic disorders;lipid regulation disorders; Congenital Leptin Deficiency; hypothalamicamenorrhea; Rabson-Mendenhall syndrome; and osteoporosis.
 3. The methodaccording to claim 1, wherein the leptin-related disease is selectedfrom the group consisting of diabetes, cardiovascular diseases, andmetabolic syndrome.
 4. The method according to claim 1, wherein theleptin-related disease is selected from the group consisting oflipodystrophy, dyslipidemia, nonalcoholic fatty liver disease,nonalcoholic steatohepatitis, and hyperlipidemia.
 5. The methodaccording to claim 1, wherein the leptin-related disease is selectedfrom the group consisting of congenital lipodystrophy, acquiredlipodystrophy, and exercise-induced hypothalamic amenorrhea.
 6. Themethod according to claim 1, wherein the NK-3 receptor antagonist isadministrated under the form of a pharmaceutical composition comprisingthe NK-3 receptor antagonist and at least one pharmaceuticallyacceptable vehicle.
 7. A method for increasing circulating leptin levelsin a patient comprising the administration of an NK-3 receptorantagonist to a patient in need thereof, wherein the NK-3 receptorantagonist is of general formula III:

or a pharmaceutically acceptable solvate thereof, wherein: R¹ is H, F ormethyl; R^(1′) is H; R² is H, F, Cl or methoxy; R^(2′) is H or F; R³ isH, F, Cl, methyl, trifluoromethyl, nitrile or R³ is thiophen-2-yl underthe condition that R⁵ is not methyl; R⁴ is methyl, ethyl, n-propyl,hydroxyethyl, methoxyethyl, trifluoromethyl, difluoromethyl orfluoromethyl; R⁵ is methyl, ethyl, methoxymethyl, trifluoromethyl,difluoromethyl, fluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl or2,2,2-trifluoroethyl; X¹ is N and X² is S or O; or X¹ is S and X² is N;

represents a single or a double bound depending on X¹ and X²; and

stands for the (R)-enantiomer or for the racemate of compound of formulaIII.